The effects of ganaxolone on neonatal seizures in hypoxic ischemic term lambs.

Abstract

Background: Seizures in neonates are relatively common, and are strong predictors of long-term cognitive and developmental impairment like cerebral palsy. Current anti-seizure therapies (phenobarbitone (pheno)) can be neurotoxic. We propose that ganaxolone (ganax), a GABAA agonist, will reduce seizures, and reduce markers of brain injury following hypoxia ischemia (HI). We investigated the effects of ganax or pheno on seizure burden and neuropathology in HI lambs. Method(s): HI was induced via umbilical cord occlusion in term lambs (n = 21; sham n = 7). HI lambs were treated with either ganax (5 mg/kg/bolus followed by 5 mg/kg/d for 2 days) or pheno (20mg/kg/bolus followed by 5 mg/kg/day for 2 days) at 6 h. Seizure burden was assessed using continuous amplitudeintegrated electroencephalogram (aEEG) recording. At 48 h, lambs were euthanized for brain collection and analysis of neuropathology. Result(s): At birth, HI lambs had a pH <7.0 and blood pressure was reduced to 16.4 +/- 1.2 mmHg, indicating severe birth asphyxia. All HI lambs demonstrated electrographic seizures; mean number of seizures/h (6-12 h) was 4.8 +/- 2.2. Ganax treatment reduced the number of seizures to 1.0 +/- 0.9/h compared to pheno (3.2 +/- 1.6/ h) (P = 0.02). Brain histology revealed improved neuronal survival (NeuN+ cell number) and reduced cell death (TUNEL+) in the cortex and basal ganglia after ganax treatment, compared to pheno (P = 0.048 and P = 0.03), respectively. Conclusion(s): Ganax treatment in lambs with HI decreased seizure activity, improved neuronal survival and reduced cell death. Ganax has a high margin of safety and proved to be a better therapy.